Heart failure (HF) is a major clinical problem in Veterans and civilians. Cardiotoxicity of cancer drugs is a type of HF that is growing in importance. Cardiotoxicity of anthracyclines, for example doxorubicin (Adriamycin), is well recognized, and cardiotoxicity is an emerging problem with novel cancer therapies, such as antibodies (trastuzumab or Herceptin) and small-molecule kinase inhibitors (sunitinib or Sutent). In 2009, ~60,000 Veterans had cancers typically treated with doxorubicin. Cardiotoxicity of cancer drugs can require discontinuation of needed cancer therapy, and cause HF even years or decades later. Although this problem is discussed extensively in recent years, no effective treatments have emerged. This project is focused on the novel idea that alpha-1A-adrenergic receptors (ARs) on cardiac myocytes comprise an endogenous adaptive signaling system that protects and repairs myocytes after injury. Alpha-1- ARs, along with beta-ARs and alpha-2-ARs, are G-protein-coupled receptors for the catecholamines norepinephrine and epinephrine. Alpha-1-ARs exist as three molecular subtypes, named A, B, and D. The idea that alpha-1A-ARs are an endogenous defense mechanism is based on direct evidence from mouse models, plus supporting evidence from multiple animal species and human clinical trials. Engaging this endogenous system with an alpha-1A agonist drug might be therapeutic to prevent cardiotoxicity of cancer drugs. Therefore, this project will test the hypothesis that drug activation of myocyte alpha-1A-ARs can prevent cancer drug cardiotoxicity. The work will take the next logical step in potential drug development, by advancing from mouse models to a large animal (rabbit) in vivo, and human ex vivo. The approach will be treatment with agonists that activate the alpha-1A-AR with high potency, efficacy, and selectivity, at a very low dose. Three specific aims are planned, organized around different experimental models. Aim I: Test whether an alpha-1A agonist protects in a rabbit model of anthracycline cardiotoxicity. Aim II: Test if alpha-1A agonists protect against different cancer drugs in human myocardial slices and cultured mouse and rat myocytes. Aim III: Test whether alpha-1A agonists reduce cancer drug efficacy in cultured cancer cells. Key aspects of experimental design include a rabbit model consistent with anthracycline dosing observed in patients; detailed analysis of cardiac damage and function throughout treatment; assay of alpha- 1A agonist drug levels in myocardium and blood; analysis of protective signaling mechanisms; and an ex vivo human myocardial slice model. Successful completion of these Aims will provide further preclinical validation of a potential novel therapy to prevent cardiotoxicity of cancer drugs, and define in a large animal a novel endogenous alpha-1A protective and adaptive mechanism in cardiac myocytes. This can be the initial step to new treatment in other forms of HF.